Metabolic dysfunction–associated steatotic liver disease: Emerging risk factors for adverse pregnancy outcomes

Abstract

Emerging evidence suggests that NAFLD, previously characterized as fatty liver disease primarily associated with obesity and insulin resistance but not excess alcohol consumption, increases the risk of adverse pregnancy outcomes in mothers and newborns. However, the precise mechanisms and contributing factors remain incompletely understood. This article offers an overview of the current epidemiological data and discusses how NAFLD and associated conditions influence the physiological changes during pregnancy, leading to complications. It also discusses potential interventions to mitigate these risks in women of reproductive age diagnosed with NAFLD, from preconception to postpartum. Although the new nomenclature, metabolic dysfunction–associated steatotic liver disease (MASLD), has replaced NAFLD and metabolic dysfunction–associated fatty liver disease,¹ we have retained the use of NAFLD and metabolic dysfunction–associated fatty liver disease in this article to align with the terms and definitions used in the literature, while incorporating MASLD when applicable.

Over the last decades, obesity has risen in US adults, climbing from 30.5% in 1999–2000 to 42.4% in 2017–2018, as reported by the National and Nutrition Examination Surveys (NHANES).² US natality data also showed that pre-pregnancy obesity among women aged 20–39, varying from 22.6% to 37.6% by state, increased significantly between 2016 and 2019, with an average increase of 11%.^3,4 This concerning trend is linked to higher risks of adverse pregnancy outcomes for both mothers and newborns, including gestational diabetes mellitus (GDM), preeclampsia, cesarean delivery, preterm delivery, macrosomia, and infant mortality (reviewed in Catalano and Ehrenberg⁵).

The data also show a rising trend of NAFLD in women of childbearing age and pregnant women, with a significant increase in NAFLD prevalence.^6,7 The prevalence of NAFLD among premenopausal women is generally low, around 9%, as reported in the Framingham Heart Study Third-Generation cohort.⁸ However, in women with polycystic ovary syndrome, which affects 5%–18% of young women (reviewed in Joham et al⁹), NAFLD can be as high as 52% (reviewed in Falzarano et al¹⁰). The precise mechanisms behind the elevated NAFLD prevalence in women with polycystic ovary syndrome are not fully understood but likely involve various metabolic and hormonal imbalances associated with the disease (eg, obesity, hyperandrogenism, insulin resistance, and diabetic mellitus).¹¹ For pregnant women, the prevalence of NAFLD was consistently around 14%–18% across the studies using ultrasonography and/or fatty liver index for the NAFLD diagnosis (Table 1).^7,16,19 A recent study by the Fatty Liver in Pregnancy Study Group found an overall NAFLD prevalence of 14% among pregnant women screened by ultrasonography in early pregnancy.¹⁹ Importantly, very few of the study subjects had a prior diagnosis of NAFLD (0.05%),¹⁹ suggesting a significant underdiagnosis of NAFLD among young women.

TABLE 1.

Epidemiological overview of associations between NAFLD/MAFLD and adverse maternal/fetal pregnancy outcomes

				Maternal adverse events (Adjusted ORs and 95% CI)a					Fetal adverse events (adjusted ORs and 95% CI)a
Author and year	Type of study and data source	MAFLD/NAFLD definitions	Size of the study population	Gestational DM	Gestational HTN	C-section	Preeclampsia	Hypertensive complications	Preterm birth	Low birth weight	Macrosomia
Hagstroem et al,12	Retrospective Swedish Medical Birth Register and National Patient Register	NAFLD by ICD codes	110 vs. 1,960,306 singleton births in NAFLD vs. non-NAFLD mothers	2.8 [1.3, 6.2]	—	1.5 [1.2, 1.9]	2.0 [1.0, 3.7]	—	2.5 [1.4, 4.6]	2.4 [1.2, 1.9]	—
De Souza et al,13	Protective A single tertiary OB clinic	NAFLD by ultrasound at 11–14 gestational weeksb	71 vs. 405 singleton births in NAFLD vs. non-NAFLD mothers	2.2 [1.1, 4.3] IFG, IGT, or GDM
Lee et al,14	Prospective OB/GYN clinics (Fatty Liver Pregnancy Registry)	NAFLD by ultrasound at 10–14 gestational weeksb	112 vs. 496 singleton births on NAFLD vs. non-NAFLD mothers	3.3 [1.5, 7.2]	—	—	—	—	—	—	—
Lee et al,15	Prospective OB/GYN clinics (Fatty Liver Pregnancy Registry)	NAFLD by ultrasound at 10–14 gestational weeksb	118 vs.505 singleton births on NAFLD vs. non-NAFLD mothers	—	—	—	—	—	—	—	3.2 [1.2, 8.6]
Jung et al,16	Prospective OB/GYN clinics (Fatty Liver Pregnancy Registry)	NAFLD by ultrasound at 10–14 gestational weeksb	137 vs. 740 singleton births on NAFLD vs. non-NAFLD mothers	—	4.3 [1.1, 14.1]	—	—	—	—	—	—
Sarkar et al,6	Retrospective United States National Inpatient Sample database	NAFLD by ICD codeb	5640 vs. 18,453,375 pregnancies in NAFLD vs. non-NAFLD mothers	(3.9)c	(1.5)c	(2.2)c	—	3.1 [2.6, 3.8]	1.6 [1.3, 2.0]	0.7 [0.4, 1.2]	1.1 [0.9, 1.5]
Lee et al,7	Retrospective National Health Insurance Service (NHIS)	Hepatic steatosis by fatty liver index of ≥30b, collected within 1 year before pregnancy	318 vs. 720,606 singleton births in NAFLD and non-FLD mothers	1.6 [1.1. 2.4]	2.0 [1.1, 3.7]	1.2 [0.9, 1.6]	—	—	1.0 [0.3, 4.1]	1.0 [0.4, 2.7]	—
			14,371 vs. 720,606 singleton births in MAFLD and non-FLD mothers (14,371)	2.9 [2.7, 3.0]	2.5 [2.3, 2.8]	2.4 [2.3, 2.5]	—	—	1.7 [1.4, 2.0]	1.4 [1.2, 1.5]	—
			27,106 vs. 720,606 singleton births in NAFLD/MAFLD and non-FLD mothers	2.6 [2.5, 2.7]	2.4 [2.2, 2.5]	1.9 [1.8, 2.0]	—	—	1.6 [1.4, 1.9]	1.1 [1.0, 1.2]	—
Qian et al,17	Retrospective A single tertiary center Antenatal and delivery database	NAFLD by ultrasound at 6–12 gestational weeksb	554 vs. 14,154 singleton births on NAFLD vs. non-NAFLD mothers	2.5 [1.9, 3.3]	3.1 [2.2, 4.3]	1.4 [1.2, 1.7]	4.0 [2.6, 6.0] Incl. eclampsia	—	1.8 [1.2, 2.7]	1.8 [1.1, 3.1]	1.7 [1.3, 2.2]
Dyah et al,18	Systematic review/meta-analysis	MAFLD, including 6 studies	5964 vs. 20,530,030 births in MAFLD vs. non-MAFLD mothers	3.7 [2.5. 5.4] Pooled ORd	3.3 [2.8, 3.9] Pooled OR	2.8 [1.6, 4.8] Pooled OR	—	—	1.7 [1.4, 2.1] Pooled OR	—	1.7 [0.6, 4.5] Pooled OR

^aAfter adjusting for age and various sets of clinical confounders, including metabolic features.

^bDocumented exclusion of chronic liver disease and excess alcohol use (or alcohol use disorder).

^cCrude OR computed using the reported numbers.

^dPregnancy-associated dysglycemia.

OR and 95% CI were rounded up due to the limited space. Bold numbers indicate statistical significance (p<0.05).

Abbreviations: DM, diabetes mellitus; FLD, fatty liver disease; HTN, hypertension; ICD, international classification of diseases; MAFLD, metabolic dysfunction–associated fatty liver disease; OB/GYN, obstetrics and gynecology.

NAFLD during pregnancy is linked to higher risks of GDM, hypertension, preeclampsia, cesarean delivery, preterm delivery, and large for gestational age/macrosomia (Table 1). Interestingly, adverse pregnancy outcomes appear more pronounced in metabolic dysfunction–associated fatty liver disease compared to NAFLD, suggesting a significant role of metabolic factors.⁷ Furthermore, some epidemiological studies revealed Body mass index (BMI)-dependent associations, where pre-pregnant BMI modifies the impacts of NAFLD on specific outcomes (eg, GDM).^12,17 Pregnancy-related changes often lead to decreased insulin sensitivity to nourish a growing fetus, and pre-existing insulin resistance, along with obesity, may exacerbate insulin resistance, elevating the risk of adverse outcomes. A retrospective cohort study further indicated that even in women with a normal pre-pregnancy BMI, NAFLD in early pregnancy raised the risk of GDM, gestational hypertension, and preeclampsia/eclampsia by 76%, 300%, and 260%, respectively, emphasizing the importance of detecting NAFLD regardless of the mother’s BMI.¹⁷

The associations between NAFLD and adverse pregnancy outcomes likely involve multiple factors. Maternal insulin resistance, measured by the homeostasis model assessment for insulin resistance, has been positively associated with placenta volume, and negatively associated with the birth weight/placental weight ratio. The above findings suggest maternal insulin resistance promotes placental growth, negatively affects placental efficiency, and may contribute to lower fetal birth weight.²⁰ During pregnancy, maternal immunity also plays a crucial role in maintaining immune tolerance to the semi-allogenic fetus and limiting immune activation. Reduced regulatory T cells relative to effector T cells, shifting toward proinflammatory IL-17 production, have been reported in women with preeclampsia compared to those with normal pregnancies.²¹ Impaired or reduced regulatory T cells and the presence of a proinflammatory cytokine environment associated with obesity and NAFLD may partly contribute to the increased risk of preeclampsia.^22,23

In summary, the sharp increase in obesity prevalence among women of childbearing age constitutes a major health care concern. Screening for MASLD in pre-pregnant women is currently insufficient. Early detection of MASLD, lifestyle intervention, weight loss, and metabolic optimization before conception for those overweight and obese are crucial for mitigating MASLD/metabolic dysfunction-associated steatohepatitis related consequences (Figure 1). For those with MASLD, education, adherence to target weight gain, closer follow-up with fasting glucose monitoring, and lifestyle intervention during pregnancy to prevent hyperglycemia are the keys to lowering the risk of adverse pregnancy outcomes (Figure 1).^25,26 Breastfeeding may offer protection against postpartum obesity and NAFLD.²⁷ Physical exercise enhances insulin sensitivity, independently of weight loss, and modulates regulatory T cells, reducing the risk of gestational weight gain, GDM, gestational hypertensive disorders, cesarean birth, preterm birth, lower birth weight, and postpartum recovery time.²⁸ Incorporating exercise into dietary plans is highly recommended. Currently, data on optimal approaches to managing NAFLD in women of reproductive age, especially during pregnancy, are limited. Further research is needed to address these critical gaps while promoting health awareness and obesity prevention among younger generations in the community.

FIGURE 1.

Preventive interventions to be considered before, during, and after pregnancy for high-risk women of childbearing age based on currently available evidence. The figure depicts interventions and preventive effects of the interventions, which may lead to improved pregnancy outcomes for both mothers and infants. Pregnancy-induced physiological insulin resistance can worsen pre-existing insulin resistance in obese mothers, increasing the risk of adverse outcomes. Therefore, preconception MASLD screening and weight loss interventions are crucial to enhance overall pregnancy outcomes. During pregnancy, early MASLD detection, adherence to weight gain targets, monitoring fasting glucose, and interventions to prevent elevated fasting glucose are essential to minimize adverse outcomes. High-risk women are advised to take low-dose aspirin to reduce the risk of preeclampsia.²⁴ Regular exercise offers multifactorial benefits and may enhance maternal and fetal outcomes. In the postpartum period, promoting breastfeeding is important for numerous advantages for both mothers and infants.²⁵ Abbreviations: DM, diabetes mellitus; MASLD, metabolic dysfunction–associated steatotic liver disease.